Abstract ND01: ABBV-303: A novel NK and CD8 T cell engager specific for c-Met-expressing tumors

Abstract Natural killer (NK) cell redirecting therapies are emerging as promising “off the shelf” treatments for cancer without the safety issues associated with T cell directed therapies. ABBV-303 is a novel c-Met targeted multispecific NK cell engager based on Dragonfly Therapeutics’ TriNKET® technology. ABBV-303 includes three functional arms: (1) a c-Met binding scFv based on ABT-700, common to c-Met-targeting antibody-drug conjugates ABBV-400 and Teliso-V; (2) a Fab arm that binds NKG2D, a stimulatory receptor expressed by NK cells and activated CD8+ T cells; and (3) a heterodimeric IgG1 Fc which binds CD16a on NK cells and links the other two binding moieties. ABBV-303 binding to NKG2D and CD16a results in redirection of both innate (NK cells) and adaptive (CD8+ T cells) immune cells to lyse c-Met expressing tumor cells. Treatment of peripheral blood mononuclear cells (PBMCs) from healthy donors and cancer patients with ABBV-303 in the presence of c-Met+ tumor cells stimulates NK and CD8+ T cells as demonstrated by modulation of activation-associated surface proteins and release of soluble factors. ABBV-303 drives sub-nanomolar redirected killing potency against tumor cells expressing a broad range of c-Met. Additionally, anti-tumor activity of ABBV-303 has been demonstrated against established xenografts in CD34 humanized NSG mice. NK and CD8+ T cell activity in response to ABBV-303 has been observed in c-Met-expressing fresh patient tumor explants. A benign safety profile was observed in non-human primates through three repeat doses up to 150 mg/kg given every two weeks, with antibody-like exposures and a serum half-life around 8 days. Based on these findings, the First in Human ABBV-303 study will initiate in 1H 2024 in solid tumors as a monotherapy and in combination with an anti-PD-1 checkpoint inhibitor. All authors are current employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Jennifer Stone, Kamonwan Pear Fish, Devika Ashok, Laura McKay, Saeed Akhand, Weilong Zhao, Si Wu, Amani Makkouk, Cormac Cosgrove, Paul Ellis, David Peetz, Stephanie Shee, Richard Peterson II, Shelby Anderson, Adam Chervin, Claudina Stevenson, Tamar Uziel, Edward Reilly. ABBV-303: A novel NK and CD8 T cell engager specific for c-Met-expressing tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr ND01.